AAV-delivered eCD4-Ig protects rhesus macaques from high-dose SIVmac239 challenges

Gardner, Matthew R.; Fellinger, Christoph H.; Kattenhorn, Lisa; Davis-Gardner, Meredith E.; Weber, Jesse A.; Alfant, Barnett; Zhou, Amber S.; Prasad, Neha R.; Kondur, Hema R.; Newton, Wendy; Weisgrau, Kimberly L.; Rakasz, Eva G.; Lifson, Jeffrey D.; Gao, Guangping; Schultz-Darken, Nancy; Farzan, Michael

doi:10.1126/scitranslmed.aau5409

Cited by 43 publications

(53 citation statements)

References 55 publications

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“…Mutations that partially compensated for this fitness loss in vitro, especially N301D, may be associated with an in vivo fitness cost because they help expose the V3 and CD4i epitopes on Env, making them more susceptible to common but usually ineffective serum antibodies. Consistent with this speculation, we have not observed mutations in the V3 loop of Envs isolated from macaques expressing eCD4-Ig (31). Even without the emergence of eCD4-Ig resistance, eCD4-Ig uniquely collaborates with such serum antibodies.…”

Section: Discussionsupporting

confidence: 87%

“…The unexpected and frequent emergence of a K171E mutation in the Env V2 apex region remains an unexplained puzzle, even more so because similar changes were observed in the Env genes isolated from SIVmac293-infected macaques expressing a rhesus form of eCD4-Ig (31). This observation raises the possibility that there is a conserved tyrosine sulfate-binding pocket at the apex that is bound by eCD4-Ig, perhaps only before induction of the CD4-bound conformation of Env.…”

Section: Discussionmentioning

confidence: 82%

“…eCD4-Ig neutralized all 270 HIV-1, HIV-2, and simian immunodeficiency virus (SIV) isolates it has been tested against, each with 80% inhibitory concentration (IC 80 ) values of less than 10 g/ml. This breadth has also been confirmed in vivo; vectored expression of eCD4-Ig fully protected rhesus macaques from SHIV-AD8 and SIVmac239 for more than 1 year, with challenges that infected all control animals (30,31). The carboxy-terminal coreceptor-mimetic peptide is critical for the breadth and potency of eCD4-Ig.…”

mentioning

confidence: 71%

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eCD4-Ig Limits HIV-1 Escape More Effectively than CD4-Ig or a Broadly Neutralizing Antibody

Fellinger

Gardner

Weber

et al. 2019

J Virol

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The engineered antibody-like entry inhibitor eCD4-Ig neutralizes every human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus isolate it has been tested against. The exceptional breadth of eCD4-Ig derives from its ability to closely and simultaneously emulate the HIV-1 receptor CD4 and coreceptors, either CCR5 or CXCR4. Here we investigated whether viral escape from eCD4-Ig is more difficult than that from CD4-Ig or the CD4-binding site antibody NIH45-46. We observed that a viral swarm selected with high concentrations of eCD4-Ig was increasingly resistant to but did not fully escape from eCD4-Ig. In contrast, viruses selected under the same conditions with CD4-Ig or NIH45-46 fully escaped from those inhibitors. eCD4-Ig-resistant viruses acquired unique changes in the V2 apex, V3, V4, and CD4-binding regions of the HIV-1 envelope glycoprotein (Env). Most of the alterations did not directly affect neutralization by eCD4-Ig or neutralizing antibodies. However, alteration of Q428 to an arginine or lysine resulted in markedly greater resistance to eCD4-Ig and CD4-Ig, with correspondingly dramatic losses in infectivity and greater sensitivity to a V3 antibody and to serum from an infected individual. Compensatory mutations in the V3 loop (N301D) and in the V2 apex (K171E) partially restored viral fitness without affecting serum or eCD4-Ig sensitivity. Collectively, these data suggest that multiple mutations will be necessary to fully escape eCD4-Ig without loss of viral fitness. IMPORTANCE HIV-1 broadly neutralizing antibodies (bNAbs) and engineered antibodylike inhibitors have been compared for their breadths, potencies, and in vivo half-lives. However, a key limitation in the use of antibodies to treat an established HIV-1 infection is the rapid emergence of fully resistant viruses. Entry inhibitors of similar breadths and potencies can differ in the ease with which viral escape variants arise. Here we show that HIV-1 escape from the potent and exceptionally broad entry inhibitor eCD4-Ig is more difficult than that from CD4-Ig or the bNAb NIH45-46. Indeed, full escape was not observed under conditions under which escape from CD4-Ig or NIH45-46 was readily detected. Moreover, viruses that were partially resistant to eCD4-Ig were markedly less infective and more sensitive to antibodies in the serum of an infected person. These data suggest that eCD4-Ig will be more difficult to escape and that even partial escape will likely extract a high fitness cost.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 71%

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eCD4-Ig Limits HIV-1 Escape More Effectively than CD4-Ig or a Broadly Neutralizing Antibody

Fellinger

Gardner

Weber

et al. 2019

J Virol

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“…Rat antisera on average neutralized more efficiently than naive sera bearing 100 µg/ml of ACE2-Ig, which itself neutralizes with an IC50 of less than 1 µg/ml, consistent with its activity against infectious SARS-CoV-1 . To provide some context for these numbers, eCD4-Ig, an immunoadhesin that emulates HIV-1 viral receptors and neutralizes with neutralization potency similar to that of ACE2-Ig, affords robust protection against high-dose intravenous challenges with an HIV-1-like virus when it is present in serum in the range of 5-10 µg/ml (Gardner et al, 2019;Gardner et al, 2015). Thus it is possible that a less robust response could still be protective.…”

Section: Discussionmentioning

confidence: 99%

The SARS-CoV-2 receptor-binding domain elicits a potent neutralizing response without antibody-dependent enhancement

Quinlan

Mou

Zhang

et al. 2020

Preprint

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138

163

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The SARS-coronavirus 2 (SARS-CoV-2) spike (S) protein mediates entry of SARS-CoV-2 into cells expressing the angiotensin-converting enzyme 2 (ACE2). The S protein engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino acid fragment of the 1273-amino acid S-protein protomer. Antibodies to the RBD domain of SARS-CoV (SARS-CoV-1), a closely related coronavirus which emerged in 2002-2003, have been shown to potently neutralize SARS-CoV-1 S-protein-mediated entry, and the presence of anti-RBD antibodies correlates with neutralization in SARS-CoV-2 convalescent sera. Here we show that immunization with the SARS-CoV-2 RBD elicits a robust neutralizing antibody response in rodents, comparable to 100 µg/ml of ACE2-Ig, a potent SARS-CoV-2 entry inhibitor. Importantly, anti-sera from immunized animals did not mediate antibodydependent enhancement (ADE) of S-protein-mediated entry under conditions in which Zika virus ADE was readily observed. These data suggest that an RBD-based vaccine for SARS-CoV-2 could be safe and effective.

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“…These antibodies have been extensively characterized in the laboratory and some have moved to clinical trials, where they have shown activity (18)(19)(20)(21)(22). They have the potential to prevent infection and also serve as a therapeutic approach complementing or even substituting antiretroviral drugs (11,14,18,(20)(21)(22)(23)(24)(25). Importantly, the use of AAV voids the need for repeated administrations of purified antibody to maintain therapeutic levels in circulation.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

et al. 2020

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Long-term delivery of anti-HIV monoclonal antibodies using adeno-associated virus (AAV) holds promise for the prevention and treatment of HIV infection. We previously reported that after receiving a single administration of AAV vector coding for anti-SIV antibody 5L7, monkey 84-05 achieved high levels of AAV-delivered 5L7 IgG1 in vivo which conferred sterile protection against six successive, escalating dose, intravenous challenges with highly infectious, highly pathogenic SIVmac239, including a final challenge with 10 animal infectious doses (1). Here we report that monkey 84-05 has successfully maintained 240-350 µg/ml of anti-SIV antibody 5L7 for over 6 years. Approximately 2% of the circulating IgG in this monkey is this one monoclonal antibody. This monkey generated little or no anti-drug antibodies (ADA) to the AAV-delivered antibody for the duration of the study. Due to the nature of the high-dose challenge used and in order to rule out a potential low-level infection not detected by regular viral loads, we have used ultrasensitive techniques to detect cell-associated viral DNA and RNA in PBMCs from this animal. In addition, we have tested serum from 84-05 by ELISA against overlapping peptides spanning the whole envelope sequence for SIVmac239 (PepScan) and against recombinant p27 and gp41 proteins. No reactivity has been detected in the ELISAs indicating the absence of naturally arising anti-SIV antibodies; moreover, the ultrasensitive cell-associated viral tests yielded no positive reaction. We conclude that macaque 84-05 was effectively protected and remained uninfected. Our data show that durable, continuous antibody expression can be achieved after one single administration of AAV and support the potential for lifelong protection against HIV from a single vector administration.

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AAV-delivered eCD4-Ig protects rhesus macaques from high-dose SIVmac239 challenges

Cited by 43 publications

References 55 publications

eCD4-Ig Limits HIV-1 Escape More Effectively than CD4-Ig or a Broadly Neutralizing Antibody

eCD4-Ig Limits HIV-1 Escape More Effectively than CD4-Ig or a Broadly Neutralizing Antibody

The SARS-CoV-2 receptor-binding domain elicits a potent neutralizing response without antibody-dependent enhancement

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

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